We have previously hypothesized that the mechanism of the antidepressant response to chronic drug therapy includes effects on the mammalian circadian system. These effects may include modifications in the expression of frequency and/or phase of the central clock that ultimately controls the expression of all circadian rhythms. Treatments that alter the frequency or phase of the central clock may change the organization of the central clock. In mammals, the circadian clock is organized as two coupled oscillators. One oscillator controls body temperature, a second oscillator controls activity and rest. Drugs may alter the circadian clock by affecting a) the oscillator controlling temperature, b) the oscillator controlling activity-rest or c) both. In this project, the effects of antidepressant drugs on the daily patterns of body temperature and activity-rest are being examined in order to determine how antidepressant drugs affect the coupled oscillator system of Syrian hamsters. Chronic inhibition of type A monoamine oxidase a) decreases the frequency of the central clock b)phase-delays the minimum hypothalamic temperature, c) decreases the level of hypothalamic temperature Syrian hamsters and d) reduces REM sleep. Inhibition of 5HT reuptake with the antidepressant drug fluoxetine also decreases hypothalamic temperature and reduces REM sleep. This suggests that 5HT mediates part of the chronic drug effects on the level of REM sleep and temperature. These observations provide evidence that antidepressant drugs with distinct pharmacological profiles alter thermoregulation when administered chronically. The effects of these drugs on the expression of the circadian pacemaker may possibly be linked by their effects on the oscillator that controls body temperature.